Physiologically Based Pharmacokinetic Modeling for Multiple Oral Administration Labetalol in Pregnant Women.

BACKGROUND: Labetalol has an irreplaceable role in treating Hypertensive disorders of pregnancy (HDP), a common disease during pregnancy with a prevalence of 5.2-8.2%. However, there were big differences in dosage regimens between various guidelines. PURPOSE: A physiologically-based pharmacokinetics (PBPK) model was established and validated to evaluate the existing oral dosage regimens, and to compare the difference in plasma concentration between pregnant and non-pregnant women. METHODS: First, non-pregnant woman models with specific plasma clearance or enzymatic metabolism (UGT1A1, UGT2B7, CYP2C19) were established and validated. For CYP2C19, slow, intermediate, and rapid metabolic phenotypes were considered. Then, a pregnant model with proper structure and parameters adjustment was established and validated against the multiple oral administration data. RESULTS: The predicted labetalol exposure captured the experimental data well. The following simulations with criteria lowering 15 mmHg blood pressure (corresponding to around 108 ng/ml plasma labetalol) found that the maximum daily dosage in the Chinese guideline may be insufficient for some severe HDP patients. Moreover, similar predicted steady-state trough plasma concentration was found between the maximum daily dosage in the American College of Obstetricians and Gynecologists (ACOG) guideline, 800 mg Q8h and a regimen of 200 mg Q6h. Simulations comparing non-pregnant and pregnant women found that the difference in labetalol exposure highly depended on the CYP2C19 metabolic phenotype. CONCLUSIONS: In summary, this work initially established a PBPK model for multiple oral administration of labetalol for pregnant women. This PBPK model may lead to personalized labetalol medication in the future.

Development and validation of a bio-analytical method for simultaneous quantification of nebivolol and labetalol in aqueous humor and plasma using LC-MS/MS and its application to ocular pharmacokinetic studies.

Beta blockers is the class of choice of drugs in treatment of open angle Glaucoma. However, many of these drugs suffer from systemic side effects due to their absorption into systemic circulation via nasolachrymal duct. To evaluate the safety and efficacy of nebivolol and labetalol for the treatment of open angle glaucoma, it is important to have a bioanalytical method for measuring the drug concentrations both in aqueous humor and plasma. A simple, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with protein precipitation technique was developed for simultaneous quantification of nebivolol and labetalol using nebivolol-d4 and metoprolol, respectively, as internal standards in aqueous humor and plasma. Nebivolol and labetalol were monitored in electrospray positive ionization (ESI) mode at transition 406.2/151.1 and 329.2/162.0, respectively. Mobile phase comprised of mixture of aqueous buffer (solvent A) and organic phase (solvent B) (mixture of A:B in the ratio of 30:70, v/v). The aqueous buffer was 5 mM ammonium acetate buffer adjusted to pH 3.5 ±â€¯0.05 with formic acid while the organic phase was a mixture of methanol and acetonitrile in the ratio of 25:75, v/v. Chromatographic separation was achieved using reverse phase Zorbax SB-C18 column (4.6 × 100 mm, 3.5 µm). Method was linear in both the matrices in the concentration range of 0.43-750 ng/mL for nebivolol and 0.39-668 ng/mL for labetalol with r2 > 0.99. Accuracy values, expressed in terms of bias (%), for nebivolol in aqueous humor and plasma were ≤9.6% and ≤11.4% and for labetalol were ≤8.6% and ≤5.9%, respectively. Inter-day and intra-day precision values, expressed in terms of RSD (%), for both the drugs were within 11.4%. No interference was obtained due to matrix components. Mean recovery (%) values in aqueous humor and plasma were 72.4% and 73.0% for nebivolol and 56.7% and 54.4% for labetalol, respectively. No significant degradation was observed in both the drugs in both the matrices when stored at -20 °C for 1 month. Aqueous humor and plasma samples of nebivolol and labetalol on bench top were stable for 18 h and 8 h, respectively. The developed method was applied for determining pharmacokinetic parameters of both drugs in aqueous humor following single dose ocular administration in rabbits.

Evaluación comparativa de dexmedetomidina y labetalol para atenuar las respuestas de estrés hemodinámico durante la colecistectomía laparoscópica en pacientes con hipertensión limítrofe / Comparative evaluation of dexmedetomidine and labetalol for attenuating hemodynamic stress responses during laparoscopic cholecystectomy in borderline hypertensive patients

Objetivo: Diversos fármacos han tratado de atenuar la respuesta vasopresora en los pacientes de colecistectomía laparoscópica. Comparamos la inyección intravenosa preinducción única de dexmedetomidina y de labetalol para atenuar la respuesta de estrés hemodinámico. Métodos: Consideramos a un total de 160 pacientes para este estudio prospectivo, aleatorizado y doble ciego, realizado en un único centro de atención terciaria. Incluimos a los pacientes en el grupo D, quienes recibieron 1μg/kg iv de dexmedetomidina, o el grupo L, quienes recibieron 0,3 mg/kg iv de labetalol en 100ml de suero salino normal antes de la inducción de anestesia. Se anotaron preoperatoriamente los parámetros hemodinámicos de los pacientes, antes de iniciar la infusión, y a intervalos fijos, hasta la extubación. Resultados: Tras la intubación, la presión arterial sistólica (PAS) fue más alta en los pacientes del grupo L (128 +/- 13,866) en comparación con el grupo D (123,2 +/- 10,672). Posteriormente, la PAS fue comparable hasta la extubación. De igual modo, tras la intubación los pacientes del grupo D tendieron a tener una presión arterial diastólica más baja (73,1 +/- 9,683 vs. 79,2 +/- 14,153, valor p de 0,0017) en comparación con los pacientes del grupo L. También la incidencia relativa de bradicardia e hipotensión fue mayor en los pacientes que habían recibido labetalol. Conclusión: En los pacientes con predisposición a fluctuaciones significativas de la presión arterial, o de la frecuencia cardiaca, la administración de dexmedetomidina puede resultar más adecuada que labetalol, debido a una mejor conservación de la hemodinámica normal, especialmente durante el periodo de estrés, habiendo reflejado una menor incidencia relativa de efectos colaterales

Objective: Various pharmacological agents have been tried to attenuate the pressor response in laparoscopic cholecystectomy patients. We have compared single pre-induction intravenous injection of dexmedetomidine with labetalol for attenuation of haemodynamic stress response. Methods: A total of 160 patients were considered for this prospective, randomized, double blind clinical study done in a single tertiary care institution. Patients were either included in group D, to receive 1.0μg·kg−1 i.v. dexmedetomidine or group L, to receive 0.3 mg·kg−1 i.v. labetalol in 100ml of normal saline before induction of anaesthesia. Patient's hemodynamic parameters were noted pre-operatively before starting infusion and at fixed intervals afterwards till extrubation. Results: After intubation, mean systolic blood pressure (SBP) was higher in patients of group L (128.0 +/- 13.866) as compared to group D (123.2 +/- 10.672). Afterwards the SBP was comparable until extrubation. Similarly, after intubation patients in group D tended to have lower diastolic pressure (73.1 +/- 9.683 vs. 79.2+/- 14.153, P value .0017) compared to patients in group L. Also, the relative incidence of bradycardia and hypotension was higher in patients who had received inj. labetalol. Conclusion: In patients predisposed to significant fluctuations in blood pressure or heart rate dexmedetomidine may be more suitable than labetalol due to better preservation of normal haemodynamics especially during periods of stress showing a relatively lower incidence of side effects

A review of oral labetalol and nifedipine in mild to moderate hypertension in pregnancy.

Hypertension is the most commonly encountered medical condition in pregnancy, contributing significantly to maternal and perinatal morbidity and mortality. Mild to moderate hypertension in pregnancy is defined as systolic blood pressure of 140-159 mmHg or diastolic blood pressure of 90-109 mmHg (7-9% of pregnancies). When treating hypertension in pregnancy, not only do physiologic changes of pregnancy have an effect on the pharmacokinetics and pharmacodynamics of the drugs used, but the pathophysiology of hypertensive disorders of pregnancy also have an effect. To date, evidence is lacking on the pharmacokinetics and pharmacodynamics of commonly used antihypertensive drugs, which often times leads to suboptimal treatment of hypertensive pregnant women. When considering which agents to use for treatment of mild to moderate hypertension, specifically in gestational and chronic hypertension, oral labetalol and nifedipine are valid options. An overview of the profile for use, safety, and current pharmacokinetic data for each agent is presented here.

Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions.

The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metabolism and solubility of a drug. However, defining the extent of metabolism relies upon clinical data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, we aimed to determine if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metabolism, to determine a reference compound representing the permeability rate above which compounds would be expected to be extensively metabolized, and to predict the major route of elimination of compounds in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calculated using ADMET Predictor or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compounds was analyzed with receiver operating characteristic curves. Compounds that yielded the highest sensitivity-specificity average were selected as permeability rate reference standards. The major route of elimination of poorly permeable drugs was predicted by our previously published model, and the accuracies and predictive values were calculated. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metabolism of compounds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco-2 and MDCK, respectively, while theophylline predicted greater than 80% of extensively and poorly metabolized drugs correctly in PAMPA. A two-tier approach predicting elimination route predicts 72 ± 9%, 49 ± 10%, and 66 ± 7% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is predicted in silico and 74 ± 7%, 85 ± 2%, and 73 ± 8% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is determined in vitro.

Influence of gestational age and body weight on the pharmacokinetics of labetalol in pregnancy.

BACKGROUND AND OBJECTIVES: Labetalol is frequently prescribed for the treatment of hypertension during pregnancy; however, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension. METHODS: Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high-performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. The final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing. RESULTS: Lean body weight (LBW) and gestational age, i.e. weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks' gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy. CONCLUSIONS: Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.

Comparison of the permeability of metoprolol and labetalol in rat, mouse, and Caco-2 cells: use as a reference standard for BCS classification.

The purpose of this study was to investigate labetalol as a potential high permeability reference standard for the application of Biopharmaceutics Classification Systems (BCS). Permeabilities of labetalol and metoprolol were investigated in animal intestinal perfusion models and Caco-2 cell monolayers. After isolating specific intestinal segments, in situ single-pass intestinal perfusions (SPIP) were performed in rats and mice. The effective permeabilities (Peff) of labetalol and metoprolol, an FDA standard for the low/high Peff class boundary, were investigated in two different segments of rat intestine (proximal jejunum and distal ileum) and in the proximal jejunum of mouse. No significant difference was found between Peff of metoprolol and labetalol in the jejunum and ileum of rat (0.33 ± 0.11 × 10(-4) vs 0.38 ± 0.06 × 10(-4) and 0.57 ± 0.17 × 10(-4) vs 0.64 ± 0.30 × 10(-4) cm/s, respectively) and in the jejunum of mouse (0.55 ± 0.05 × 10(-4) vs 0.59 ± 0.13 × 10(-4) cm/s). However, Peff of metoprolol and labetalol were 1.7 and 1.6 times higher in the jejunum of mouse, compared to the jejunum of rat, respectively. Metoprolol and labetalol showed segmental-dependent permeability through the rat intestine, with increased Peff in the distal ileum in comparison to the proximal jejunum. Most significantly, Peff of labetalol was found to be concentration-dependent. Decreasing concentrations of labetalol in the perfusate resulted in decreased Peff compared to Peff of metoprolol. The intestinal epithelial permeability of labetalol was lower than that of metoprolol in Caco-2 cells at both apical pH 6.5 and 7.5 (5.96 ± 1.96 × 10(-6) vs 9.44 ± 3.44 × 10(-6) and 15.9 ± 2.2 × 10(-6) vs 23.2 ± 7.1 × 10(-6) cm/s, respectively). Labetalol exhibited higher permeability in basolateral to apical (BL-AP) compared to AP-BL direction in Caco-2 cells at 0.1 times the highest dose strength (HDS) (46.7 ± 6.5 × 10(-6) vs 14.2 ± 1.5 × 10(-6) cm/s). The P-gp inhibitor, verapamil, significantly increased AP-BL and decreased BL-AP direction transport of labetalol. Overall, labetalol showed high Peff in rat and mouse intestinal perfusion models similar to metoprolol at a concentration based on HDS. However, the concentration-dependent permeability of labetalol in mice due to P-gp and the inhibition study with verapamil in Caco-2 cells indicated that labetalol is not an ideal reference standard for BCS classification.

CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects.

PURPOSE: The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol. METHODS: The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms. RESULTS: Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0 ± 66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞. CONCLUSION: Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.

Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage.

PURPOSE: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs. METHODS: The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis. RESULTS: Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app). CONCLUSIONS: Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.

Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients.

PURPOSE: This study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally. METHODS: Thirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol. RESULTS: The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the ß-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the α-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women. CONCLUSIONS: The approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the α-blocking activity of this isomer.

In vitro and in vivo assessment of matrix type transdermal therapeutic system of labetalol hydrochloride.

OBJECTIVE: The aim of the investigation was to develop and evaluate matrix type transdermal therapeutic systems containing new polymeric combinations (Eudragit E PO/Eudragit RL 100 & Plasdone S 630) as polymers and Labetalol Hydrochloride (LBHCl) as a model drug. EXPERIMENTAL: The matrix type TTS of LBHCl were prepared by film casting technique. The patches were characterized for physical, in vitro release studies & ex-vivo permeation studies (human cadaver skin). On the basis of in vitro drug release and skin permeation performance, formulation A1 was found to be better than the other formulations and it was selected as the optimized formulation. The optimized patch was assessed for its pharmacokinetic, pharmacodynamic, skin irritation potential, and stability studies. RESULTS: The maximum percentage drug release & Permeation in 48 hrs were 92.43 % and 76.24 % respectively for optimized patch. The Korsmeyer peppas release exponent value of 0.604 suggested release mechanism towards first order release in the optimized formulation. The results obtained from the in vivo characterization of the optimized patch showed sustained action of the developed formulation. The interaction studies analysis indicated no chemical interaction between the drug and polymers. The optimized patch was seemingly free of potentially hazardous skin irritation as suggested by skin irritation score of 0.915<2.00 (under Draize score test). The optimized formulation was found to be stable at ambient storage conditions. CONCLUSION: The above TTS holds promise for improved bioavailability and better management of hypertension on long term basis.

Basil oil is a promising skin penetration enhancer for transdermal delivery of labetolol hydrochloride.

The present work investigates effectiveness of basil oil, a volatile oil containing alcoholic terpenes, as a potential penetration enhancer for improved skin permeation of labetolol hydrochloride (LHCl) with reference to camphor, geraniol, thymol, and clove oil. Saturation solubilities of LHCl were determined in water, vehicle (ethanol:water, 60:40 v/v) and vehicle containing 5% w/v terpenes. Comparable (P > 0.05) saturation solubilities were found suggesting an insignificant increase in LHCl flux across rat skin on account of thermodynamic activity. Permeation of LHCl in vehicle per se and in presence of 5% w/v enhancer was investigated by performing in vitro rat abdominal skin permeation studies using a side-by-side glass diffusion cell. Various parameters viz. steady state flux, permeability coefficient, lag time, partition coefficient, diffusion coefficient, and enhancement ratios (ER) were calculated from the permeation data. Basil oil produced the maximum enhancement (ER = 46.52) over neat vehicle, among all enhancers. Activation energies for LHCl permeation in water, vehicle per se and in presence of 5% w/v basil oil were found to be 23.16, 18.71, and 10.98 kcal/mole, respectively. Lowering of activation energy in presence of basil oil suggests creation of new polar pathways in the skin for enhanced permeation of LHCl. Basil oil is proposed as a promising penetration enhancer for improved transdermal drug delivery of labetolol.

Labetalol absorption kinetics: rat small intestine and colon studies.

Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the intestine (1.42 +/- 0.05/h) and the colon (1.13 +/- 0.06/h), V(m) and K(m) of the input process (9.85 +/- 4.98 microM/h, and 10.44 +/- 26.16 microM, respectively) and K(m) of an efflux system (0.53 +/- 1.16 microM) and V(m) in both intestinal segments (2.60 +/- 11.37 microM . /h in the intestine and 0.66 +/- 1.38 microM . /h in the colon). The efflux carrier implicated is identified by means of several inhibition experiments, whose inhibition ability is mathematically estimated. Results suggest the p-glycoprotein as responsible for the efflux of labetalol.

Transdermal drug delivery of labetolol hydrochloride: system development, in vitro; ex vivo and in vivo characterization.

OBJECTIVE: The aim of the present work was to develop and evaluate matrix type transdermal drug delivery systems (TDDS) of labetolol hydrochloride (L-HCL) effective for 48 hours. EXPERIMENTAL: The TDDS were prepared by solvent evaporation technique. Six formulations (carrying Eudragit RL100:Eudragit RS 100 in 7.5:4.5, 5.0:5.0, 3.5:8.5 in formulations X-1, X-2, X-3 and Eudragit RL100:PVP K-30 in 9.0:2.0, 5.0:5.0, 4.0:7.0 in formulations Y-1, Y-2, Y-3, respectively) were prepared. All formulations carried 36% w/w of L-HCL, 10-12% w/w of enhancer dimethyl sulfoxide and 2.5-7.5% w/w of plasticizer PEG 400 in methanol-acetone solvent system. The TDDS were evaluated by in vitro drug release, ex vivo skin permeation, stability and in vivo pharmacodynamic studies. RESULTS: The maximum drug release for X-series was 90.26% in 48 hours (X-1) and for Y-series, it was 83.24% (Y-1). Again formulations X-1 (Kp = 0.221x10(-2) cm hr(-1)) and Y-1 (Kp = 0.210x10(-2) cm hr(-1)) exhibited the best skin permeation potential in the respective series. This might be due to higher permeability characteristics of Eudragit RL100. A shelf life of 2.38 years was predicted for the TDDS. Mean systolic BP of the experimental hypertensive rats was significantly reduced (p<0.01) on TDDS treatment. CONCLUSION: The TDDS holds promise for clinical trials.

Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs.

STUDY OBJECTIVE: To evaluate the impact of gender on labetalol kinetics. DESIGN: Part of a randomized, crossover study. SETTING: Academic medical center. PATIENTS: Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites). INTERVENTIONS: Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. MEASUREMENTS AND MAIN RESULTS: Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]/dose x 1000: 6.79 +/- 2.11 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/dose x 1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hr/L (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/- 3.08 hr/L (NS). CONCLUSION: The higher labetalol concentration in women than in men was explained largely by differences in inactive and alpha1-blocking stereoisomers. However, concentrations were similar between genders for the beta-blocking stereoisomer (R,R-labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.

AIMS: Obesity can modify the pharmacokinetics of lipophilic drugs. As beta-adrenoceptor blockers (BB) are often prescribed for obese patients suffering from hypertension or coronary heart disease, this study compares the pharmacokinetics of lipophilic beta-adrenoceptor blockers in obese and control subjects. METHODS: Nine obese (157 +/- 24% of ideal body weight (IBW) mean +/- s.d.) and nine non-obese healthy volunteers (98 +/- 10% IBW), aged 32 +/- 9 years, were included in the study. Subjects were randomly given a single i.v. infusion of one of the following racemic beta-adrenoceptor blockers, whose doses (expressed as base per kg of IBW) were: propranolol (0.108 mg), labetalol (0.99 mg) and nebivolol (0.073 mg). The plasma concentrations of unchanged drugs were measured by h.p.l.c. The ionisation constants and lipophilicity parameters of beta-adrenoceptor blockers were assessed. RESULTS: The pharmacokinetic data for the three drugs were qualitatively similar. There was a trend towards a greater total distribution volume (Vss) in obese patients than in controls. However, Vss expressed per kg body weight was slightly smaller in obese patients. The relationship between Vss and lipophilicity of five beta-adrenoceptor was studied by combining the current results with those previously obtained with a moderately lipophilic drug (bisoprolol) and a hydrophilic one (sotalol). The Vss of the five drugs was positively and well-correlated (r2 = 0.90; P < 0.01) with their distribution coefficient at pH 7.4 (log D7.4), but not with their partition coefficients. The linear regression coefficients for lean and obese subjects were very similar. CONCLUSIONS: Lipophilic beta-adrenoceptor blockers seem to diffuse less into adipose than into lean tissues. All electrical forms of the drugs (i.e. cations, neutral forms, or zwitterions) present at physiological pH contribute to their tissue distribution, in both obese and lean subjects. Their tissue distribution in obese patients could be restricted by the sum of hydrophobic forces and hydrogen bonds they elicit with macromolecules in lean tissues.

Sensitive chiral high-performance liquid chromatographic assay for labetalol in biological fluids.

The four stereoisomers of the combined alpha- and beta-adrenoceptor antagonist labetalol were separated and quantified at therapeutic concentrations by normal-phase high-pressure liquid chromatography using a chiral stationary phase and fluorescence detection. Drug in plasma or urine was recovered by solid-phase extraction with 83+/-5% efficiency. Limits of detection from biological samples (3 ml) were between 1.5-1.8 ng ml(-1). Intra-day and inter-day variation at 25 ng ml(-1) were < or = 2.7% and < or = 5.80% respectively for all stereoisomers. The assay was applied to an examination of the disposition of labetalol stereoisomers after a single oral dose of racemate to a human volunteer. Labetalol appears to undergo enantioselective metabolism leading to relatively low plasma concentrations of the pharmacologically active enantiomers.